Humans grafted with allogeneic bone marrows stem cells at 12-13 weeks of age will develop stable and long lasting chimerism. This hypothesis derives from the observation that T cells do not peripheralize from the human fetal thymus until 14 weeks of gestation, together with the finding that animals grafted with stem cells, before they have T cells develop specific immunologic tolerance. Thus, it may be possible to correct a range of congenital disorders by stem cell transplant prior to irreversible damage. Our response to the RFA focuses on humans because this is the area in which we have specific strengths. Fetuses homozygous for alpha thalassemia (a hemoglobinopathy causing fetal hydrops) will be identified by the Genetics service in Hawaii using an Hba chain specific PCR applied to chorionic villous biopsies obtained at 8-10 weeks gestation. Families with affected fetuses will be offered entry subject to specific criteria and admitted to the CRC at UCHSC by the 12th week of gestation. Marrow will be drawn from an appropriate donor, processed to deplete T cells and enrich for stem cells and then injected into the umbilical vein of affected fetuses at 12-13 weeks. Pregnancies will be monitored every 7 days through week 26 by ECHO. A fetal blood sample (FBS) will be obtained at 19-20 weeks and tested for Hb type and for chimerism by PCR. Fetuses with <10 g/dL of Hb will be transfused with packed red cells. A fetal blood sample will be obtained at 26-28 weeks from surviving fetuses and tested for Hb type, chimerism and alloantigen- specific tolerance. No further treatment will be attempted for fetuses who are not chimeric at this point. Chimeric fetuses will be supported as required through 34-36 weeks and then delivered. Surviving newborns will be retested for chimerism in the erythroid and white cell series, along with the degree of tolerance or alloreactivity. Fetuses who were transfusion dependent at 36-34 weeks will be retransplanted in the newborn period. Our studies will test our underlying hypothesis and will therefore generate data on which fetal grafts of genetically engineered cells might be based.
| Hayward, A; Ambruso, D; Battaglia, F et al. (1998) Microchimerism and tolerance following intrauterine transplantation and transfusion for alpha-thalassemia-1. Fetal Diagn Ther 13:8-14 |
